Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1α-VEGF axis

Rationale: Bronchial inflammation is usually accompanied by increased vascular permeability. Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. Vascular endothelial growth factor (VEGF) has been implicated to contribute to asthmatic tissue edema through its effect on vascular permeability. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood. Objectives: An aim of the present study was to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease. Methods: We used genetically mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-v) (W/W-v) mice and the congenic normal WBB6F(1)(+/+) mouse model for allergic airway disease to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease, more specifically in vascular permeability. Measurements and Main Results: Our present study, with ovalbumin (OVA)-sensitized without adjuvant and OVA-challenged mice, revealed the following typical pathophysiologic features of allergic airway diseases: increased inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of VEGF. However, levels of VEGF and plasma exudation in W/W-v mice after OVA inhalation were significantly lower than levels in WBB6F(1)(+/+) mice. Moreover, mast cell-reconstituted W/W-v mice restored vascular permeability and VEGF levels similar to those of the WBB6F(1)(+/+) mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation through the phosphatidylinositol 3-kinase (PI3K)-HIF-1 alpha pathway in allergic airway disease. Conclusions: These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K-HIF-1 alpha-VEGF axis.